Process for producing isatoic anhydrides

ABSTRACT

A process for producing isatoic anhydrides of the formula (II): ##STR1## which comprises reacting an anthranilic acid of formula (I): ##STR2## or a salt thereof with phosgene using a mixed solvent of water and an organic solvent miscible with water and inert to the reaction; 
     conducting the reaction in the coexistence of an alkylpyridinium salt in an aqueous solvent; or 
     using a mixed solvent of water and a specific amount of an organic solvent substantially immiscible with water and inert to the reaction.

This a divisional of application Ser. No. 08/773,357 filed Dec. 26, 1996U.S. Pat. No. 5,795,984.

The present invention relates to a process for producing isatoicanhydrides. More particularly, it relates to a process for producingisatoic anhydrides using corresponding anthranilic acid or a saltthereof and phosgene.

Isatoic anhydrides are useful as an intermediate of an antiphlogistic, aremedy for diabetic complication, etc as described in U.S. Pat. Nos.4,734,429 and 4,883,800. As the production process, for example, thereis known that isatoic anhydrides are produced by using correspondinganthranilic acid or a salt thereof and phosgene in the presence of awater solvent (J. Org. Chem., 26, 613 (1961)).

However, the above process using water as the solvent had an industrialproblem that the reaction mixture changes into a whipped cream stateand, therefore, a volume efficiency of a reactor is very low and anyield of the objective product is not satisfactory.

The present inventors have intensively studied about the process forproducing isatoic anhydrides so as to solve these drawbacks.

As a result, it has been found that, by using a mixed solvent consistingof water and an organic solvent which is miscible with water and isinert to the reaction, in place of water conventionally used as thereaction solvent, it becomes possible to inhibit the formation ofwhipped cream mass from the reaction mixture, thereby remarkablyimproving not only the volume efficiency of the reactor but also theyield.

The present inventors have also found, by coexisting a specificcompound, an alkylpyridinium salt, in the reaction, inhibitation of theformation of whipped cream mass from the reaction mixture, that is, theremarkable improvment of volume efficiency of the reactor as well as ofthe yield, can be attained.

The present inventors have further found that, by using a mixed solventconsisting of water and a specific amount of an organic solvent which issubstantially immiscible with water and is inert to the reaction inplace of water conventionally used as the reaction solvent, it is alsopossible to solve the above-mentioned problems of the conventionalmethod.

Thus, the present invention has been accomplished.

That is, the present invention provides a process for producing isatoicanhydrides represented by the formula (II): ##STR3## wherein R₁ and R₂independently indicate a hydrogen atom, a halogen atom, a nitro group, alower alkyl group which is optionally substituted with a halogen atom,an aralkyl group which is optionally substituted with a halogen atom, analkoxy group which is optionally substituted with a halogen atom, analkoxycarbonyl group which is optionally substituted with a halogenatom, an acyloxy group or XNR₄ R₅ (X is a direct bond, a lower alkylenegroup or a carbonyl group provided that, when X is a direct bond or alower alkylene group, R₄ and R₅ independently indicate a lower alkylgroup or N, R₄ and R₅ may form a five- or six-membered heterocycle whichoptionally contain another hetero atom and, when X is a carbonyl group,R₄ and R₅ independently indicate a hydrogen atom or a lower alkyl groupor N, R₄ and R₅ may form a five- or six-membered heterocycle whichoptionally contain another hetero atom and further, when containinganother hetero atom, said hetero atom may be substituted.); and R₃ is ahydrogen atom, a halogen atom, a nitro group, a lower alkyl group whichis optionally substituted with a halogen atom, an aralkyl group which isoptionally substituted with a halogen atom, an alkoxy group which isoptionally substituted with a halogen atom or an alkoxycarbonyl groupwhich is optionally substituted with a halogen atom,

which comprises reacting phosgene

and an anthranilic acid represented by the formula (I): ##STR4## whereinR₁, R₂ and R₃ are as defined above, or a salt thereof using a mixedsolvent of water and an organic solvent which is miscible with water andinert to the reaction.

The present invention also provides a process for producing an isatoicanhydride compound of the formula (II) which comprises reacting phosgeneand an anthranilic acid compound of the formula (I) or a salt thereof inthe coexistence of an alkylpyridinium salt.

The present invention further provides a process for producing anisatoic anhydride compound of the formula (II) which comprises reactingphosgene and an anthranilic acid compound of the formula (I) or a saltthereof using a mixed solvent of water and an organic solvent which issubstantially immiscible with water and inert to the reaction, theamount of the organic solvent being in a range of 1.5-20 fold by weightor more with respect to the amount of an anthranilic acid compound ofthe formula (I) or a salt thereof.

Hereinafter, the present invention will be described in detail.

The substituents R₁ and R₂ in anthranilic acids (I) as the raw materialof the present invention independently indicate a hydrogen atom, ahalogen atom, a nitro group, a lower alkyl group which is optionallysubstituted with a halogen atom, an aralkyl group which is optionallysubstituted with a halogen atom, an alkoxy group which is optionallysubstituted with a halogen atom, an alkoxycarbonyl group which isoptionally substituted with a halogen atom, an acyloxy group or XNR₄ R₅(X is a direct bond, a lower alkylene group or a carbonyl group providedthat, when X is a direct bond or a lower alkylene group, R₄ and R₅independently indicate a lower alkyl group or N, R4 and R₅ may form afive- or six-membered heterocycle which optionally contain anotherhetero atom and, when X is a carbonyl group, R₄ and R₅ independentlyindicate a hydrogen atom or a lower alkyl group or N, R₄ and R₅ may forma five- or six-membered heterocycle which optionally contain anotherhetero atom and further, when containing another hetero atom, saidhetero atom can be substituted.); and R₃ is a hydrogen atom, a halogenatom, a nitro group, a lower alkyl group which is optionally substitutedwith a halogen atom, an aralkyl group which is optionally substitutedwith a halogen atom, an alkoxy group which is optionally substitutedwith a halogen atom or an alkoxycarbonyl group which is optionallysubstituted with a halogen atom.

Examples of the halogen atom include chlorine, bromine and fluorine.

Examples of the lower alkyl group which is optionally substituted withthe halogen atom include lower alkyl group such as methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl and hexyl;monohalo lower alkyl group such as chloromethyl, bromomethyl andchloropropyl; dihalo lower alkyl group such as 1,2-dichloroethyl,1,2-dibromoethyl and, 2,2-dichloroethyl; and trihalo lower alkyl groupsuch as trifluoromethyl.

Examples of the aralkyl group which is optionally substituted with thehalogen atom include benzyl, phenylethyl, 4-chlorobenzyl,2,4-dichlorobenzyl and 2,4-dibromobenzyl.

Examples of the alkoxy group which is optionally substituted with thehalogen atom include lower alkoxy group such as methoxy, ethoxy,propoxy, i-propoxy, butoxy, i-butoxy, t-butoxy, pentyloxy, i-pentyloxy,hexyloxy, etc.; and lower alkoxy group substituted with the halogenatom, such as chloromethoxy, bromomethoxy, 1-, 2-chloroethoxy, 1-, 2-,3-chloropropoxy, dichloromethoxy, dibromomethoxy, 1,2-dichloroethoxy,2,2-dichloroethoxy and trifluoromethoxy.

Examples of the alkoxycarbonyl group which is optionally substitutedwith the halogen atom include the same carbonyl group having the alkoxygroup which is optionally substituted with the halogen atom as describedabove.

Examples of the acyloxy group include lower alkylcarbonyloxy group suchas acetoxy, propionyloxy, butyryloxy, i-butyryloxy, valeryloxy,i-valeryloxy and pivaloyloxy, and arylcarbonyloxy group such asbenzoyloxy.

Examples of the lower alkylene group in XNR4R5 include methylene,dimethylene, trimethylene and tetramethylene. Examples of R4 and R5 asthe lower alkyl group in NR4R5 include the same lower alkyl group asdescribed above. Specific examples thereof include dimethylamino,diethylamino, dipropylamino and dibutylamino.

Specific examples of a five- or six-membered heterocycle formed by N, R4and R5 in case that N, R4 and R5 in NR4R5 form a heterocycle whichoptionally have another hetero atom are pyrrolyl, 2H,4H-pyrrolyl,pyrrolidino, pyrazolyl, piperidino, morpholino and imidazolyl.

When another hetero atom is N, N can have a substituent. Examples of thesubstituent include the same lower alkyl group which is optionallysubstituted with the halogen atom as described above, the same aralkylgroup which is optionally substituted with the halogen atom as describedabove, aralkyl group substituted with a lower alkoxy group and aphenylcarbonyl group which is optionally substituted with a lower alkoxygroup.

Typical examples of the anthranilic acids (I) include anthranilic acid,3-, 4-, 5-, 6-chloroanthranilic acid, 3-, 4-, 5-, 6-bromoanthranilicacid, 3-, 4-, 5-, 6-fluoroanthranilic acid, 3,4-, 3,5-, 3,6-, 4,5-,5,6-dichloroanthranilic acid, 3,4-, 3,5-, 3,6-, 4,5-,5,6-dibromoanthranilic acid, 3,4-, 3,5-, 3,6-, 4,5-,5,6-difluoroanthranilic acid, 3-bromo-4-chloroanthranilic acid,3-bromo-5-chloroanthranilic acid, 3-bromo-6-chloroanthranilic acid,4-bromo-3-chloroanthranilic acid, 4-bromo-5-chloroanthranilic acid,4-bromo-6-chloroanthranilic acid, 5-bromo-3-chloroanthranilic acid,5-bromo-4-chloroanthranilic acid, 5-bromo-6-chloroanthranilic acid,6-bromo-3-chloroanthranilic acid, 6-bromo-4-chloroanthranilic acid,6-bromo-5-chloroanthranilic acid, 3-chloro-4-fluoroanthranilic acid,3-bromo-4-fluoroanthranilic acid, 3,4,5-, 3,4,6-, 3,5,6-,4,5,6-trichloroanthranilic acid, 3,4,5-, 3,4,6-, 3,5,6-,4,5,6-tribromoanthranilic acid, 3,4,5-, 3,4,6-, 3,5,6-,4,5,6-trifluoroanthranilic acid, 3-, 4-, 5-, 6-nitroanthranilic acid,3-, 4-, 5-, 6-methylanthranilic acid, 3-, 4-, 5-, 6-ethylanthranilicacid, 3-, 4-, 5-, 6-propylanthranilic acid, 3-, 4-, 5-,6-i-propylanthranilic acid, 3-, 4-, 5-, 6-methoxycarbonylanthranilicacid, 3-, 4-, 5-, 6-ethoxycarbonylanthranilic acid, 3-, 4-, 5-,6-propoxycarbonylanthranilic acid, 3-, 4-, 5-,6-i-propoxycarbonylanthranilic acid, 3-, 4-, 5-,6-t-butoxycarbonylanthranilic acid, 3-, 4-, 5-,6-(chloromethoxy)anthranilic acid, 3-, 4-, 5-,6-(bromomethoxy)anthranilic acid, 3-, 4-, 5-,6-(1-chloroethoxy)anthranilic acid, 3-, 4-, 5-,6-(2-chloroethoxy)anthranilic acid, 3-, 4-, 5-,6-(1-chloropropoxy)anthranilic acid, 3-, 4-, 5-,6-(2-chloropropoxy)anthranilic acid, 3-, 4-, 5-,6-(3-chloropropoxy)anthranilic acid, 3-, 4-, 5-,6-(dichloromethoxy)anthranilic acid, 3-, 4-, 5-,6-(dibromomethoxy)anthranilic acid, 3-, 4-, 5-,6-(trifluoromethoxy)anthranilic acid, 3-, 4-, 5-,6-(chloromethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(bromomethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(1-chloroethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(2-chloroethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(1-chloropropoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(dichloromethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(dibromomethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(1,2-dichloromethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(2,2-dichloromethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-(trifluoromethoxycarbonyl)anthranilic acid, 3-, 4-, 5-,6-chloromethylanthranilic acid, 3-, 4-, 5-, 6-bromomethylanthranilicacid, 3-, 4-, 5-, 6-(1-chloroethyl)anthranilic acid, 3-, 4-, 5-,6-chloroethyl)anthranilic acid, 3-, 4-, 5-,6-(dichloromethyl)anthranilic acid, 3-, 4-, 5-,6-(1,2-chloroethyl)anthranilic acid, 3-, 4-, 5-,6-(2,2-dichloroethyl)anthranilic acid, 3,4-dimethylanthranilic acid,3,4-diethylanthranilic acid, 3-benzylanthranilic acid, 3-(2-phenylethyl) anthranilic acid, 3-(4-chlorobenzyl)anthranilic acid,3-(2,4-dichlorobenzyl) anthranilic acid,3-(2,4-dibromobenzyl)anthranilic acid, 3-methoxyanthranilic acid,3-ethoxyanthranilic acid, 3- propoxyanthranilic acid,3-i-propoxyanthranilic acid, 4,5-dimethoxyanthranilic acid,5,6-dimethoxyanthranilic acid, 3,5-diethoxyanthranilic acid,3,6-dipropoxyanthranilic acid, 3-(N,N-dimethylamino)anthranilic acid,3-(N,N-diethylamino)anthranilic acid, 3-(N,N-dipropylamino)anthranilicacid, 3-(N,N-dibutylamino)anthranilic acid, 3-(1-pyrrolyl) anthranilicacid, 3-(1-imidazolyl)anthranilic acid, 3-(1-pyrazolyl)anthranilic acid,3-(2H,4H-pyrrolyl)anthranilic acid, 3-(piperidino)anthranilic acid,3-(morpholino)anthranilic acid, 3-(4-methylpiperidino)anthranilic acid,3-(4-(chloromethyl)piperidino)anthranilic acid,3-(4-benzylpiperidino)anthranilic acid,3-(4-(3-methoxybenzyl)piperidino)anthranilic acid,3-(4-(phenylcarbonylpiperidino)anthranilic acid,5-(4-(3,4-dimethoxyphenylcarbonyl)piperidino)anthranilic acid,3-(1-pyrrolylmethyl)anthranilic acid, 3-(morpholinomethyl)anthranilicacid, 4-((4-methylpiperidino)methyl)anthranilic acid,phenylcarbonylpropyl)piperidinocarbonyl)anthranilic acid,4,6-dimethyl-5-ethyloxycarbonyl anthranilic acid, 3-carbamoylanthranilicacid, 3-(N-methylcarbamoyl) anthranilic acid,3-(N,N-dimethylcarbamoyl)anthranilic acid, 4-(4-methylpiperidinocarboxy)anthranilic acid, 5-(4-benzylpiperidinocarboxy)anthranilic acid,5-(4-(3-phenylcarbonylpropyl)piperidinocarboxy)anthranilic acid,4,6-dimethyl-5-ethyloxycarbonylanthranilic acid,3-chloro-5,6-dimethoxyanthranilic acid, 4-acetoxyanthranilic acid,4-propionyloxyanthranilic acid, 4-butyryloxyanthranilic acid,4-i-butyryloxyanthranilic acid, 4-valeryloxyanthranilic acid,4-i-valeryloxyanthranilic acid, 4-pivaloyloxyanthranilic acid and4-benzoyloxyanthranilic acid.

The anthranilic acids (I) can also be used in the form of a salt. Eitherthe amino group or the carboxyl group may form a salt. Examples of thesalt include hydrochloride salt, sodium salt and potassium salt.

The object of the present invention can be attained by using a mixedsolvent consisting of water and an organic solvent which is misciblewith water and is inert to the reaction in place of water as thereaction solvent. (Hereinafter this method is referred to as Method 1.)Examples of the organic solvent which is miscible with water and isinert to the reaction include cyclic ethers such as tetrahydrofuran,dioxane; and glymes such as ethylene glycol dimethyl ether anddiethylene glycol dimethyl ether. Among them, cyclic ethers,particularly tetrahydrofuran, are preferred,.

The proportion of the organic solvent in the mixed solvent variesdepending on the kind of anthranilic acid, the raw material, and kind ofisatoic anhydride, the product, but is normally from 1 to 99% by weight,preferably from 5 to 95% by weight, more preferably from 10 to 90% byweight, further more preferably from 10 to 50% by weight, based on thetotal amount of the mixed solvent.

When the proportion of the organic solvent is less than 1% by weight,the effect of inhibiting the formation of whipped cream mass from thereaction mixture is liable to be lowered. Therefore, normally, not lessthan 1% by weight of the mixed solvent is used.

An amount of the mixed solvent used is normally from 1- to 20-foldamount by weight, preferably from 2- to 10-fold amount by weight, withrespect to the amount of anthranilic acids.

The object of the present invention can also be attained by reacting theanthranilic acid compound of the formula (I) or a salt thereof withphosgene in the coexistence of an alkylpyridinium salt in an aqueoussolvent. (Hereinafter this method is referred to as Method 2.) Examplesof the alkylpyridinium salt include compounds represented by thefollowing formula (III): ##STR5## wherein R₆ indicates an alkyl grouphaving 8-20 carbon atoms, R₇ indicates a hydrogen atom or a lower alkylgroup and X indicates an anion.

Examples of the alkyl group having 8-20 carbon atoms as R₆ includen-octyl, 2-ethylhexyl, nonyl decyl, i-decyl, undecyl, lauryl, tridecyl,myristyl, palmityl, stearyl and eicosyl. Examples of the lower alkylgroup as R₇ include methyl, ethyl, propyl, i-propyl, butyl and pentyl.

X includes, for example, halogen anions such as chloride and bromide,sulfonyloxy anions such as methanesulfonyloxy, benzenesulfonyloxy andp-toluenesulfonyloxy.

Typical examples of the alkylpyridinium salt include laurylpyridiniumchloride, laurylpyridinium bromide, cetylpyridinium chloride,cetylpyridinium bromide, myristyl-γ-picolium chloride andlauryl-γ-picolium benzenesulfonate.

The alkylpyridinium salt is used usually in about 0.005-0.5 fold amountby weight, preferably about 0.01-0.2 fold amount by weight, morepreferably about 0.05-0.2 fold amount by weight, with respect to theamount of anthranilic acid compound of the formula (I).

In method 2, water, the reaction solvent, is used usually in about 1-20fold amount by weight, preferably about 2-10 fold amount by weight, withrespect to the amount of anthranilic acid compound of formula (I).

Further, in Method 2, an organic solvent substantially immiscible withwater and inert to the reaction may be co-used as the solvent.

Examples of the organic solvent include aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such aschlorobenzene, o-dicnlorobenzene, m-dichlorobenzene, bromobenzene,dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; and ethers such as ethylether and di-i-propylether.Among them, aromatic hydrocarbons, halogenated hydrocarbons and thelike, particularly toluene, chlorobenzene and the like, are preferred.

In method 2, the amount of the organic solvent, when used, is usuallyabout 0.01-1 fold by weight, preferably about 0.1-0.5 fold by weight,with respect to the amount of water.

The object of the present invention can also be attained by using amixed solvent consisting of water and an organic solvent which issubstantially immiscible with water and is inert to the reaction inplace of water as the reaction solvent. (Hereinafter this method isreferred to as Method 3.) The amount of the organic solvent is in arange of 1.5-20 fold by weight, preferably 2.0-10-fold by weight, withrespect to the amount of an anthranilic acid compound of the formula (I)or a salt thereof.

Examples of the organic solvent include aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such aschlorobenzene, o-dichlorobenzene, m-dichlorobenzene, bromobenzene,dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; and ethers such as ethylether and di-i-propylether.Among them, aromatic hydrocarbons, halogenated hydrocarbons and thelike, particularly toluene, chlorobenzene and the like, are preferred.

In Method 1, Method 2 and Method 3, the anthranilic acids or a saltthereof is dissolved or dispersed in the reaction solvent and,thereafter, is reacted with phosgene. The reaction is normally carriedout by introducing phosgene into a reactor while adjusting the pH of thereaction mixture to about 2 to 10, preferably from about 3 to 9, morepreferably about 6 to 7. The reaction temperature is normally from 0 to40° C., preferably from 0 to 20° C.

For adjusting the pH, an alkaline is normally used. Examples of thealkaline include alkali metal hydroxide such as sodium hydroxide andpotassium hydroxide; alkali earth metal hydroxide such as magnesiumhydroxide, calcium hydroxide and barium hydroxide; alkali metalcarbonate such as sodium carbonate and potassium carbonate; alkali earthmetal carbonate such as magnesium carbonate, calcium carbonate andbarium carbonate; alkali metal hydrogencarbonate such as sodiumhydrogencarbonate and potassium hydrogencarbonate; and alkali earthmetal oxide such as calcium oxide and barium oxide. Among them, sodiumhydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate and calciumhydrogencarbonate are preferably used.

The alkalines can be used singly or as a mixture of two or more thereof.The alkaline can be used after mixing with water.

In both Method 1 and Method 2, phosgene may be introduced in a vaporstate or introduced in a liquid state under pressure. It is alsopossible to introduce phosgene dissolved in the organic solvent.

An introducing inlet of phosgene may be at the vapor phase part orliquid phase part of the reactor. When the introducing inlet is at theliquid phase, isatoic anhydrides are sometimes deposited to close theintroducing inlet. Therefore, the reaction must be carried out takingthis point into consideration.

An amount of phosgene introduced is normally from about 0.9- to 2-foldmolar amount, preferably from about 1- to 1.7-fold molar amount, withrespect to the anthranilic acids.

It is preferred that, firstly, a predetermined amount of phosgene wasintroduced while maintaining the pH of the reaction mixture at 2 to 10,and, then, remaining phosgene or a mineral acid such as hydrochloricacid is added thereto until the pH becomes 2 or lower, preferably 1 orlower, thereby making it possible to improve the yield of the objectiveproduct.

Thus, the objective isatoic anhydrides are produced. When isatoicanhydrides are removed from the reaction mixture, phosgene remained isnormally exhausted in the first place. Examples of such a exhaustionprocess include a process of purging an inert gas such as nitrogen, aprocess of distilling off with a solvent, and a process of adding analcohol such as methanol to react with phosgene. It is possible toobtain isatoic anhydrides by distilling off the organic solvent from thereaction mixture after exhaustion of phosgene, followed by subjecting toseparating means such as filtration.

The isatoic anhydrides thus obtained can also be further purified, ifnecessary.

According to the present invention, Method 1, Method 2 and Method 3, itbecomes possible to inhibit the formation of whipped cream mass from thereaction mixture and the volume efficiency of the reactor is improved,thereby remarkably improving the productivity. It becomes also possibleto improve yield of isatoic anhydrides, the objective product.

The following Examples further illustrate the present invention indetail but are not to be construed to limit the scope thereof.

EXAMPLE 1

To a 200 ml flask equipped with a condenser (-20° C.), water (43.5 g),tetrahydrofuran (43.5 g) and 4-chloroanthranilic acid (4.38 g, purity:98%) were charged. After cooling to 10° C. with stirring, sodiumcarbonate was added thereto so that the pH became 6 to 7. Then, thereaction was conducted while introducing phosgene in the vapor phasepart of a reactor with a flow rate of 0.2 g/minute, cooling the reactionmixture so that the temperature was maintained at 20 to 25° C., andadding an aqueous 10% sodium carbonate so that the pH was maintained at6 to 7.

After 3 g of phosgene has been introduced, the addition of the aqueoussodium carbonate was stopped and phosgene was further introducedcontinuously until the pH became 1. The maximum value of the volume ofthe reaction mixture was 180 ml.

After the completion of the reaction, the reaction mixture was heated to65° C. and, after distilling off phosgene together with a part of thesolvent, the resultant crystal was filtered, washed with methanol andthen dried to obtain 4.4 g of 7-chloroisatoic anhydride (purity: 99%).The yield was 88%.

The volume efficiency (yield of the objective product per maximum volume100 ml of the reaction mixture) was 2.4 g/100 ml.

EXAMPLE 2

To a 2 liter flask equipped with a condenser (-20° C.), water (510 g),tetrahydrofuran (51 g) and 4-chloroanthranilic acid (106 g, purity: 98%)were charged. After cooling to 10° C. with stirring, an aqueous 23%sodium hydroxide was added thereto so that the pH became 6 to 7. Then,the reaction was conducted while introducing phosgene in a vapor phasepart of a reactor with a flow rate of 0.5 g/minute, cooling the reactionmixture so that the temperature was maintained at 5 to 15° C. and addingan aqueous 23% sodium hydroxide so that the pH was maintained at 6 to 7.

After 67 g of phosgene has been introduced, the addition of the aqueoussodium hydroxide was stopped and phosgene was further introducedcontinuously until the pH became 1. The maximum value of the volume ofthe reaction mixture was 1100 ml.

According to the same manner as in Example 1, the reaction mixture waspost-treated to obtain 116 g of 7-chloroisatoic anhydride (purity: 99%).The yield was 97% and the volume efficiency was 10.5 g/100 ml.

COMPARATIVE EXAMPLE 1

According to the same manner as in Example 1 except that the volume ofthe flask was changed to 1 liter and water (87 g) was used in place ofwater and tetrahydrofuran, the reaction was conducted. The maximum valueof the volume of the reaction mixture was 350 ml.

According to the same manner as in Example 1, the reaction mixture waspost-treated to obtain 4.12 g of 7-chloroisatoic anhydride (purity:99%). The yield was 83% and the volume efficiency was 1.2 g/100 ml.

EXAMPLE 3

Into a 200 ml flask equipped with a cooling apparatus (-20° C.) wereplaced 53 g of water, 2.8 g of laurylpyridinium chloride and 18 g of4-chloroanthranilic acid (purity: 98%). The mixture was cooled to 10° C.with stirring and adjusted to pH 6-7 with addition of an aqueous sodiumhydroxide. Then, the reaction was conducted while introducing phosgeneinto the vapor phase part of the reactor at a flow rate of 0.3 g/minute,cooling the reaction mixture so as to maintain the temperature at 5-15°C. and adding an aqueous sodium hydroxide such that pH was maintained at6-7.

When 23 g of phosgene was introduced, addition of the aqueous sodiumhydroxide was stopped and introduction of phosgene was further continueduntil pH became 1.

After completion of the reaction, excess phosgene was exhausted byaddition of methanol and crystals were filtered, washed with methanoland dried to give 18.5 g of 7-chloroisatoic anhydride (purity: 98%). Theconversion of 4-chloroanthranilic acid was 98% and the yield was 91%.

The volume efficiency (yield of the objective product per maximum volume100 ml the reaction mixture) was 10 g/100 ml.

EXAMPLE 4

According to the same manner as in Example 3, except that 17 g oftoluene and 2.9 g of laurylpyridinium chloride were used in place of 2.8g of laurylpyridinium chloride and the flow rate of phosgene introducedwas changed to 0.2 g/minute, 19.6 g of 7-chloroisatoic anhydride(purity: 99.7%) was obtained.

The conversion of 4-chloroanthranilic acid was 100%, the yield was 91%and the volume efficiency was 12 g/100 ml.

COMPARATIVE EXAMPLE 2

According to the same manner as in example 3, except that the flask waschanged to 1 l flask, 88 g of water was added in place of water andlaurylpyridinium chloride, an aqueous sodium carbonate was used in placeof the aqueous sodium hydroxide and phosgene was changed to 5.2 g, 4.1 gof 7-chloroisatoic anhydride (purity: 99%) was obtained.

The conversion of 4-chloroanthranilic acid was 83%, the yield was 20%and the volume efficiency was 1.2 g/100 ml.

COMPARATIVE EXAMPLE 3

The same manner as in Example 3 was conducted, except that phosgene wasintroduced without addition of laurylpyridinium chloride. The reactionmixture became a whipped cream mass with an increase in volume, therebyblocking the cooling apparatus. Therefore, the reaction was stopped whenabout 10 g of phosgene was introduced.

The conversion of 4-chloroanthranilic acid was 33%.

COMPARATIVE EXAMPLE 4

According to the same manner as in Example 4, except that the flask waschanged to 300 ml flask, laurylpyridinium chloride was not used, 103 gof water was added, and that amounts of toluene, phosgene and4-chloroanthranilic acid were changed to 34 g, 40 g and 35 g,respectively, 35.6 g of 7-chloroisatoic anhydride (purity: 73.8%) wasobtained. The yield was 67% and the volume efficiency was 9 g/100 ml.

COMPARATIVE EXAMPLE 5

According to the same manner as in Example 3 except thatlaurylpyridinium chloride was replaced by 1.7 g of sodium laurylbenzenesulfonate and the amount of phosgene was changed to 30 g,7-chloroisatoic anhydride was obtained.

The conversion of 4-chloroanthranilic acid was 69% and the yield was64%.

COMPARATIVE EXAMPLE 6

According to the same manner as in Example 3, except thatlaurylpyridinium chloride was replaced by 2.28 g of benzyl triethylammonium chloride and the amount of phosgene was changed to 30 g,7-chloroisatoic anhydride was obtained.

The conversion of 4-chloroanthranilic acid was 73%.

EXAMPLE 5

To a 200 ml flask equipped with a condenser (-20° C.), water (78.9 g),tetrahydrofuran (315.5 g) and 4,5-dimethoxyanthranilic acid (80.5 g,purity: 98%) were charged. After cooling to 20° C. with stirring, anaqueous 25% sodium hydroxide solution was added thereto so that the pHbecame 6 to 7. Then, the reaction was conducted while introducingphosgene in the vapor phase part of a reactor with a flow rate of 0.26g/minute, cooling the reaction mixture so that the temperature wasmaintained at 15 to 25° C., and adding an aqueous 25% sodium hydroxidesolution so that the pH was maintained at 6 to 7.

After 47.5 g of phosgene has been introduced, the addition of theaqueous sodium hydroxide and phosgene was stopped and 18% hydrochloricacid (11.7 g) was added so that the pH became 1.

According to the same manner as that in Example 3, a post treatment wascarried out to obtain 79.6 g of 6,7-dimethoxyisatoic anhydride (purity:88%). The yield was 83%.

EXAMPLE 6

According to the same manner as in Example 5, except that 171.6 g ofwater and 171.6 g of toluene were used in place of 78.9 g of water and315.5 g of tetrahydrofuran, and that 4-chloroanthranilic acid was usedin place of 4,5-dimethoxyanthranilic acid, 80.9 g of 7-chloroisatoicanhydride (purity: 91%) was obtained.

The yield was 93%.

EXAMPLE 7

According to the same manner as in Example 3, except that the flask waschanged to 500 ml flask, 70 g of water, 280 g of toluene and 35 g of4-chloroanthranilic acid were in place of 53 g of water and 2.8 g oflaurylpyridinium chloride, and that the reaction temperature wasmaintained at 15-25° C., 41.0 g of 7-chloroisatoic anhydride (purity:94%) was obtained.

The yield was 98%.

What is claimed is:
 1. A process for producing isatoic anhydridesrepresented by formula (II): ##STR6## wherein R₁ and R₂ each represent ahydrogen atom, a halogen atom, a nitro group, a lower alkyl group whichis optionally substituted with a halogen atom, an aralkyl group which isoptionally substituted with a halogen atom, an alkoxy group which isoptionally substituted with a halogen atom, an alkoxycarbonyl groupwhich is optionally substituted with a halogen atom, an acyloxy group orXNR₄ R₅ (wherein X is a direct bond, a lower alkylene group or acarbonyl group provided that, when X is a direct bond or a loweralkylene group, R₄ and R₅ each represent a lower alkyl group or N, R₄and R₅ may form a five- or six-membered heterocycle which optionallycontain another hetero atom and, when X is a carbonyl group, R₄ and R₅each represent a hydrogen atom or a lower alkyl group or N, R₄ and R₅may form a five- or six-membered heterocycle which optionally containanother hetero atom and further, when containing another hetero atom,said hetero atom may be substituted); and R₃ is a hydrogen atom, ahalogen atom, a nitro group, a lower alkyl group which is optionallysubstituted with a halogen atom, an aralkyl group which is optionallysubstituted with a halogen atom, an alkoxy group which is optionallysubstituted with a halogen atom or an alkoxycarbonyl group which isoptionally substituted with a halogen atom, which comprises the step ofreacting phosgene and an anthranilic acid represented by the formula(I): ##STR7## wherein R₁, R₂ and R₃ are as defined above, or a saltthereof using a mixed solvent of water and an organic which is misciblewith water and inert to the reaction, the reaction being carried out byintroducing phosgene into the reactor while adjusting the pH of thereaction mixture to about 6 to 7, wherein the mixed solvent is used in a1- to 20-fold amount by weight relative to the anthranilic acid offormula (I) or salt thereof, and a proportion of the organic solvent inthe mixed solvent is from 10 to 50% by weight.
 2. The process accordingto claim 1, wherein the organic solvent is at least one solvent selectedfrom the group consisting of cyclic ethers or glymes.
 3. The processaccording to claim 2, wherein the cyclic ether is tetrahydrofuran.